304
8 Peptide Hormones
hormonally active ~ subunit of nerve growth factor (NGF) is produced as a dimer by the sensory
and sympathetic neuron target tissues. The submandibular glands of mice contain a 230-kDa
complex (7S-NGF) made up of two a chains, a
~ chain, two y chains and one or two zinc atoms.
Based on their sequences, the a and y chains
belong to the kallikrein families of the serine proteases, although the a chain is proteolytically
inactive. The 7S-NGF and similar complexes
from other tissues do not bind to the NGF receptor and their biological significance is not clear
[136]. The brain-derived neurotrophic factor
(BDNF) of the rat and NT-3 of mice are homologous to NGF; the three sequences have 48 % of
their amino acids in common (130). The murine
prepro-NGF of 307 amino acids includes the
118 amino acids of the mature ~-NGF sequence in
positions 188-305. The corresponding human
chain differs in 11 amino acids, the bovine chain
in 16 amino acids, and that of the chicken in 19
amino acids. NGFs are also found in snake
venoms but their sequences are, at present,
largely unknown.
The epidermal growth factors (EGFs) have
lengths of between 48 and 53 amino acids
(Fig. 8.2m). The rat EGF sequence of 48 amino
acids shows 77 % agreement with the murine
EGF (53 amino acids), 69 % with the human
sequence (53 amino acids), and only 67 % with
the guinea-pig EGF (51 amino acids) [205]. Surprisingly, the EGF precursor is anchored in the
cell membrane and contains within its 1200 amino
acids the real EGF and eight EGF-like sequences. The EGF receptor is an integral membrane
protein of 1186 amino acids with many N-linked
oligosaccharide chains. Similarly to other growth
factor receptors, the cytoplasmic domain of the
EGF receptor has tyrosine kinase activity; this
represents the beginning of a complex signal
transduction pathway [30]. DNA sequences have
been identified in Drosophila which encode polypeptides similar to the tyrosine kinase and the
extracellular domain of the human EGF receptor
[227]. The EGFfamily includes further GFs
which bind to the EGF receptor despite their low
sequence similarity, e.g. human amphiregulin,
the transforming growth factor TGF-a, and the
pox virus growth factor (VGF). On the other
hand, TGF-~, which has also been detected in
Drosophila eggs and embryos [11], constitutes a
distinct family of multifunctional regulatory peptides [44]. EGF-like sequences are found in many
proteins of both vertebrates and invertebrates,
and present a particularly impressive example of
the importance of exon shuffling in the evolution
of proteins: 1 such sequence is found in tissue
plasminogen activator and urokinase, 2 sequences are found in the clotting factors IX and X, 3 in
the low density lipoprotein (LDL) receptor, 11 in
the gene "lin" of the nematode Caenorhabditis
elegans, at least 18 in the gene "uEGF-1" of the
sea urchin Strongylocentrotus lividus, and 36 in
the gene "notch" of Drosophila melanogaster and
the related gene "xotch" from Xenopus laevis.
There are other peptides with regulatory
effects on cell growth and differentiation: one of
the most interesting of these peptides is the head
activator of the freshwater polyp Hydra; this defines the anterior end during regeneration. It is an
undecapeptide (Fig. 8.2 n) which not only occurs
in Hydra and other Cnidaria but, remarkably, is
also found in the gut and hypothalamus of the rat
and man [16, 192]. The growth of blood vessels in
mammals is stimulated by angiogenin, a homologue of the pancreas RNase [19]. The differentiation of fibroblasts to myoblasts is controlled by
three related peptides known as myogenin, myoD
and myf5 [64]. A structurally and functionally
very similar factor, SUM-1, arises as the translation product of an mRNA from the sea urchin
Lytechinus variegatus [222]. A bovine boneinducing protein has been isolated and is referred
to as the osteogenic protein (OP) [110]. Prothymosin a is an acidic peptide of 110 amino acids,
found in many mammalian tissues, and has
immuno-enhancing effects. The first substance of
this type to be found, thymosin a, from calf thymus, corresponds to the 28 N-terminal amino
acids of prothymosin at and is probably an extraction artefact. Parathymosin, isolated from rat
thymus, is antagonistic to prothymosin a and has
15 % sequence similarity [229]. Thymosin at-like
substances have been detected immunologically
in insects, crustaceans, protozoans, lower fungi
and even bacteria [157]. The homologous proteins thymosine ~4' ~9 and ~1O form a distinct family
of immuno-modulatory peptides [229].
s.s Peptide Hormones of Invertebrates
Peptide hormones are in fact found in all groups
of invertebrates but have so far been mainly
investigated in the molluscs and arthropods.
Because of problems in obtaining sufficient
quantities, their isolation and characterization
has proved difficult. However, the development
of more sensitive methods of peptide sequencing,
8 Peptide Hormones
hormonally active ~ subunit of nerve growth factor (NGF) is produced as a dimer by the sensory
and sympathetic neuron target tissues. The submandibular glands of mice contain a 230-kDa
complex (7S-NGF) made up of two a chains, a
~ chain, two y chains and one or two zinc atoms.
Based on their sequences, the a and y chains
belong to the kallikrein families of the serine proteases, although the a chain is proteolytically
inactive. The 7S-NGF and similar complexes
from other tissues do not bind to the NGF receptor and their biological significance is not clear
[136]. The brain-derived neurotrophic factor
(BDNF) of the rat and NT-3 of mice are homologous to NGF; the three sequences have 48 % of
their amino acids in common (130). The murine
prepro-NGF of 307 amino acids includes the
118 amino acids of the mature ~-NGF sequence in
positions 188-305. The corresponding human
chain differs in 11 amino acids, the bovine chain
in 16 amino acids, and that of the chicken in 19
amino acids. NGFs are also found in snake
venoms but their sequences are, at present,
largely unknown.
The epidermal growth factors (EGFs) have
lengths of between 48 and 53 amino acids
(Fig. 8.2m). The rat EGF sequence of 48 amino
acids shows 77 % agreement with the murine
EGF (53 amino acids), 69 % with the human
sequence (53 amino acids), and only 67 % with
the guinea-pig EGF (51 amino acids) [205]. Surprisingly, the EGF precursor is anchored in the
cell membrane and contains within its 1200 amino
acids the real EGF and eight EGF-like sequences. The EGF receptor is an integral membrane
protein of 1186 amino acids with many N-linked
oligosaccharide chains. Similarly to other growth
factor receptors, the cytoplasmic domain of the
EGF receptor has tyrosine kinase activity; this
represents the beginning of a complex signal
transduction pathway [30]. DNA sequences have
been identified in Drosophila which encode polypeptides similar to the tyrosine kinase and the
extracellular domain of the human EGF receptor
[227]. The EGFfamily includes further GFs
which bind to the EGF receptor despite their low
sequence similarity, e.g. human amphiregulin,
the transforming growth factor TGF-a, and the
pox virus growth factor (VGF). On the other
hand, TGF-~, which has also been detected in
Drosophila eggs and embryos [11], constitutes a
distinct family of multifunctional regulatory peptides [44]. EGF-like sequences are found in many
proteins of both vertebrates and invertebrates,
and present a particularly impressive example of
the importance of exon shuffling in the evolution
of proteins: 1 such sequence is found in tissue
plasminogen activator and urokinase, 2 sequences are found in the clotting factors IX and X, 3 in
the low density lipoprotein (LDL) receptor, 11 in
the gene "lin" of the nematode Caenorhabditis
elegans, at least 18 in the gene "uEGF-1" of the
sea urchin Strongylocentrotus lividus, and 36 in
the gene "notch" of Drosophila melanogaster and
the related gene "xotch" from Xenopus laevis.
There are other peptides with regulatory
effects on cell growth and differentiation: one of
the most interesting of these peptides is the head
activator of the freshwater polyp Hydra; this defines the anterior end during regeneration. It is an
undecapeptide (Fig. 8.2 n) which not only occurs
in Hydra and other Cnidaria but, remarkably, is
also found in the gut and hypothalamus of the rat
and man [16, 192]. The growth of blood vessels in
mammals is stimulated by angiogenin, a homologue of the pancreas RNase [19]. The differentiation of fibroblasts to myoblasts is controlled by
three related peptides known as myogenin, myoD
and myf5 [64]. A structurally and functionally
very similar factor, SUM-1, arises as the translation product of an mRNA from the sea urchin
Lytechinus variegatus [222]. A bovine boneinducing protein has been isolated and is referred
to as the osteogenic protein (OP) [110]. Prothymosin a is an acidic peptide of 110 amino acids,
found in many mammalian tissues, and has
immuno-enhancing effects. The first substance of
this type to be found, thymosin a, from calf thymus, corresponds to the 28 N-terminal amino
acids of prothymosin at and is probably an extraction artefact. Parathymosin, isolated from rat
thymus, is antagonistic to prothymosin a and has
15 % sequence similarity [229]. Thymosin at-like
substances have been detected immunologically
in insects, crustaceans, protozoans, lower fungi
and even bacteria [157]. The homologous proteins thymosine ~4' ~9 and ~1O form a distinct family
of immuno-modulatory peptides [229].
s.s Peptide Hormones of Invertebrates
Peptide hormones are in fact found in all groups
of invertebrates but have so far been mainly
investigated in the molluscs and arthropods.
Because of problems in obtaining sufficient
quantities, their isolation and characterization
has proved difficult. However, the development
of more sensitive methods of peptide sequencing,